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EGFR-Targeted Therapy in Metastatic Colorectal Cancer

Panelists: John L. Marshall, MD, Georgetown University; Bert H. ONeil, MD, Indiana University School of Medicine; Marwan Fakih, MD, City of Hope Comprehensive Care Center; Gabriela Chiorean, MD, University of Washington School of Medicine; Wells A. Messersmith, MD, FACP, University of Colorado Cancer Center
Published: Wednesday, Sep 05, 2018



Transcript: 

Wells A. Messersmith, MD, FACP: I think separating the fact that if you don’t give an EGFR, for instance, either first-line or just for a few cycles, really what harm is being done? And we have to remember, in RAS-mutated patients, in many of the studies, there’s a pretty good trend toward harm if they’re RAS-mutated. And that’s not to mention, of course, for a 1.7 m2 person, the $5700 cost. At some point, we are going to have to be thinking about the cost of these things. So from my standpoint …

John L. Marshall, MD: But I get a 70% response rate. I want a response in this woman.

Wells A. Messersmith, MD, FACP: Absolutely, and these are the kind of people for whom I might use FOLFOXIRI or FOLFIRINOX because I think you’re going for reasons. And it’s really important to be clear about what the goals of therapy are because I see people, who have absolutely no symptoms, get triple therapy, and I’m like, are we trying to make the CT scan look pretty, or are we trying to prolong the survival of the patient? And you sometimes see a less aggressive approach, where response can be really helpful for somebody who’s having pain or about to obstruct. I agree with you, I don’t like stents, just like to get the chemotherapy going.

John L. Marshall, MD: Well, I worry those are the ones that have had perforations lately. That’s the only reason. They look great, but I worry about perforations.

Wells A. Messersmith, MD, FACP: Absolutely, and you certainly wouldn’t want to give. For someone who might have to have emergent surgery, you do not want bevacizumab or ramucirumab onboard, so that’s something to think about as well.

John L. Marshall, MD: So I gave her FOLFOXIRI through a peripheral line because apparently you can’t get a port over a holiday weekend or a PICC in our hospital. So that’s just a shout-out, and then waiting on this because I wanted that response. Back to Wells’s point. This is a little off our main topic, but I’ve been thinking a lot about this issue of regimens and proved benefit, where we decide that it’s too toxic or it’s not the right thing to do. And I think one of the 2 examples is the FOLFOXIRI/bevacizumab study, the TRIBE study, which showed a survival response, PFS benefit, but was toxic. So we don’t give it even though it was a positive study. And the same thing is true for left-sided RAS wild-type colon cancers where we have really big deltas in those retrospective analyses, but we say we don’t like the rash. Where do we get off being so paternalistic or maternalistic, saying that we’re not going to offer you this proved survival response-rate benefit because of toxicity? What do you think about our behavior there?

Gabriela Chiorean, MD: Well, I think that oftentimes we do take into account what the goals of care are. And I think that if, again, response rate is a consideration and especially if I have a KRAS-mutant patient, I would never hesitate considering a FOLFOXIRI. We’re very well versed on how to manage FOLFOXIRI and FOLFIRINOX today.

John L. Marshall, MD: But even in that asymptomatic patient, I almost never think to give that.

Gabriela Chiorean, MD: I think that in asymptomatic patients, because again we have so many lines of therapies and so many good clinical trials, we don’t want to disqualify, potentially, patients to participate and new agents coming onboard all the time. I think we sometimes worry that patients will become, again, resistant in time, and they may not have access to something novel down the line.

John L. Marshall, MD: Yes, we spend it all too soon. But even though those studies say that there was an OS benefit, that’s what I struggle with. Some of this, to me, is also just complex for the practice to manage one of these regimens, whether it’s the additional rash toxicity or the myelosuppression and diarrhea of the triple-drug therapy. Wells?

Wells A. Messersmith, MD, FACP: Yes. Just to make the point, in many of those studies and actually in pharmacy databases, I think one of the nice things about all these computerized records is hopefully we can get data from tens of thousands of patients. But many patients don’t get second-line therapy. When they look at the pharmacy database and when they look at those trials, a lot of patients don’t get second-line therapy. And at least in my practice, everyone gets second-line therapy and everyone gets third-line therapy pretty much unless something horrible happens. So one of the reasons I feel comfortable with it is because I know that, and based on my practice, people are going to get exposed to all the drugs. I don’t have to worry that they’re not going to get any second-line therapy. In many of those trials, over half the patients got nothing else. So yes, if your plan is to give nothing else, you should probably give that. But short of that, I think you can feel a little bit more comfortable doling it out in terms of the side effects and be a little more judicious with the drugs.

Marwan Fakih, MD: I have to say, John, that some of us have actually endorsed that data.

John L. Marshall, MD: Yay!

Marwan Fakih, MD: So to me, 4 or 5 months’ difference in overall survival for left colon with the anti-EGFR therapy is something important.

John L. Marshall, MD: It’s hard not to leave that on the table, right?

Marwan Fakih, MD: No, you don’t, and you discuss this with patients. And patients are receptive. And let’s face it, they’re going to get that anti-EGFR at some point in their treatment. And the truth is, even when you implement it in the first-line setting, a lot of times you’re not pushing it necessarily much more than 6 months because a lot of issues may arise, hypomagnesium or some skin toxicities that the patients want to do without. And so maybe that downstaging is important, and so our practice now has moved to basically stratify by left, right. And if it’s a RAS wild-type, BRAF wild-type, they get the anti-EGFR in the first-line setting.

John L. Marshall, MD: You know, you bring up that question because there’s a study being presented here. If you started with, in this case, panitumumab in front line, what do you do in the maintenance setting? Just kind of keep plowing along, or do you switch over to the VEGF-based?

Wells A. Messersmith, MD, FACP: Do you want a $6 drug or a $6000 drug as your maintenance approach?

John L. Marshall, MD: Well, what’s the $6 drug?

Wells A. Messersmith, MD, FACP: 5-FU.

John L. Marshall, MD: Ah.

Wells A. Messersmith, MD, FACP: Leucovorin is $61. And you’re right, you have to put …

John L. Marshall, MD: Well, I think the data are with capecitabine, I would say, so that’s not a cheap drug. And the data are with bevacizumab, too, which is not a cheap drug either.

Wells A. Messersmith, MD, FACP: Yes, true.

John L. Marshall, MD: But do you maintain the EGFR therapy through that or switch? What’s your thought on that?

Marwan Fakih, MD: I do maintain if it’s tolerated by patients. I like to mention the VALENTINO trial showed a PFS of 13 months versus 10 months, and that was statistically significant.

John L. Marshall, MD: So you drop the chemotherapy and just give single-agent EGF?

Marwan Fakih, MD: I drop. I still use FOLFOX in my first-line approach, and I drop oxaliplatin after 4 months of treatment, and then they’re maintained on fluoropyrimidine and anti-EGFR. Now, I do switch biologicals if they have a problem with anti-EGFR toxicity. So if I see the magnesium level is dropping and I can’t keep up with the replacement or it becomes a nuisance to the patient, certainly I have no problems at all at that point, dropping anti-EGFR and switching to fluoropyrimidine-bevacizumab.

John L. Marshall, MD: You know how I’ve solved hypomagnesaemia?

Marwan Fakih, MD: How?

John L. Marshall, MD: I don’t check it. It just goes away. It’s no longer a problem. That’s a good strategy. You just don’t look.

Marwan Fakih, MD: But I’ll tell you, I’ve seen some 0.4s gone.

Wells A. Messersmith, MD, FACP: VALENTINO though looked at continuing panitumumab plus 5-FU versus panitumumab. So it’s the 5-FU that’s the 3-month benefit, not the panitumumab.

Marwan Fakih, MD: But I have to say, 13 months is quite an impressive PFS.

Wells A. Messersmith, MD, FACP: It is, I agree.

Marwan Fakih, MD: So there’s a signal there.

Wells A. Messersmith, MD, FACP: What you’re saying is you are a FIRE believer and not a CALGB/SWOG 80405 believer.

Marwan Fakih, MD: Well, CALGB/SWOG 80405 left colon RAS is not that far from FIRE-3.

Transcript Edited for Clarity 

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Transcript: 

Wells A. Messersmith, MD, FACP: I think separating the fact that if you don’t give an EGFR, for instance, either first-line or just for a few cycles, really what harm is being done? And we have to remember, in RAS-mutated patients, in many of the studies, there’s a pretty good trend toward harm if they’re RAS-mutated. And that’s not to mention, of course, for a 1.7 m2 person, the $5700 cost. At some point, we are going to have to be thinking about the cost of these things. So from my standpoint …

John L. Marshall, MD: But I get a 70% response rate. I want a response in this woman.

Wells A. Messersmith, MD, FACP: Absolutely, and these are the kind of people for whom I might use FOLFOXIRI or FOLFIRINOX because I think you’re going for reasons. And it’s really important to be clear about what the goals of therapy are because I see people, who have absolutely no symptoms, get triple therapy, and I’m like, are we trying to make the CT scan look pretty, or are we trying to prolong the survival of the patient? And you sometimes see a less aggressive approach, where response can be really helpful for somebody who’s having pain or about to obstruct. I agree with you, I don’t like stents, just like to get the chemotherapy going.

John L. Marshall, MD: Well, I worry those are the ones that have had perforations lately. That’s the only reason. They look great, but I worry about perforations.

Wells A. Messersmith, MD, FACP: Absolutely, and you certainly wouldn’t want to give. For someone who might have to have emergent surgery, you do not want bevacizumab or ramucirumab onboard, so that’s something to think about as well.

John L. Marshall, MD: So I gave her FOLFOXIRI through a peripheral line because apparently you can’t get a port over a holiday weekend or a PICC in our hospital. So that’s just a shout-out, and then waiting on this because I wanted that response. Back to Wells’s point. This is a little off our main topic, but I’ve been thinking a lot about this issue of regimens and proved benefit, where we decide that it’s too toxic or it’s not the right thing to do. And I think one of the 2 examples is the FOLFOXIRI/bevacizumab study, the TRIBE study, which showed a survival response, PFS benefit, but was toxic. So we don’t give it even though it was a positive study. And the same thing is true for left-sided RAS wild-type colon cancers where we have really big deltas in those retrospective analyses, but we say we don’t like the rash. Where do we get off being so paternalistic or maternalistic, saying that we’re not going to offer you this proved survival response-rate benefit because of toxicity? What do you think about our behavior there?

Gabriela Chiorean, MD: Well, I think that oftentimes we do take into account what the goals of care are. And I think that if, again, response rate is a consideration and especially if I have a KRAS-mutant patient, I would never hesitate considering a FOLFOXIRI. We’re very well versed on how to manage FOLFOXIRI and FOLFIRINOX today.

John L. Marshall, MD: But even in that asymptomatic patient, I almost never think to give that.

Gabriela Chiorean, MD: I think that in asymptomatic patients, because again we have so many lines of therapies and so many good clinical trials, we don’t want to disqualify, potentially, patients to participate and new agents coming onboard all the time. I think we sometimes worry that patients will become, again, resistant in time, and they may not have access to something novel down the line.

John L. Marshall, MD: Yes, we spend it all too soon. But even though those studies say that there was an OS benefit, that’s what I struggle with. Some of this, to me, is also just complex for the practice to manage one of these regimens, whether it’s the additional rash toxicity or the myelosuppression and diarrhea of the triple-drug therapy. Wells?

Wells A. Messersmith, MD, FACP: Yes. Just to make the point, in many of those studies and actually in pharmacy databases, I think one of the nice things about all these computerized records is hopefully we can get data from tens of thousands of patients. But many patients don’t get second-line therapy. When they look at the pharmacy database and when they look at those trials, a lot of patients don’t get second-line therapy. And at least in my practice, everyone gets second-line therapy and everyone gets third-line therapy pretty much unless something horrible happens. So one of the reasons I feel comfortable with it is because I know that, and based on my practice, people are going to get exposed to all the drugs. I don’t have to worry that they’re not going to get any second-line therapy. In many of those trials, over half the patients got nothing else. So yes, if your plan is to give nothing else, you should probably give that. But short of that, I think you can feel a little bit more comfortable doling it out in terms of the side effects and be a little more judicious with the drugs.

Marwan Fakih, MD: I have to say, John, that some of us have actually endorsed that data.

John L. Marshall, MD: Yay!

Marwan Fakih, MD: So to me, 4 or 5 months’ difference in overall survival for left colon with the anti-EGFR therapy is something important.

John L. Marshall, MD: It’s hard not to leave that on the table, right?

Marwan Fakih, MD: No, you don’t, and you discuss this with patients. And patients are receptive. And let’s face it, they’re going to get that anti-EGFR at some point in their treatment. And the truth is, even when you implement it in the first-line setting, a lot of times you’re not pushing it necessarily much more than 6 months because a lot of issues may arise, hypomagnesium or some skin toxicities that the patients want to do without. And so maybe that downstaging is important, and so our practice now has moved to basically stratify by left, right. And if it’s a RAS wild-type, BRAF wild-type, they get the anti-EGFR in the first-line setting.

John L. Marshall, MD: You know, you bring up that question because there’s a study being presented here. If you started with, in this case, panitumumab in front line, what do you do in the maintenance setting? Just kind of keep plowing along, or do you switch over to the VEGF-based?

Wells A. Messersmith, MD, FACP: Do you want a $6 drug or a $6000 drug as your maintenance approach?

John L. Marshall, MD: Well, what’s the $6 drug?

Wells A. Messersmith, MD, FACP: 5-FU.

John L. Marshall, MD: Ah.

Wells A. Messersmith, MD, FACP: Leucovorin is $61. And you’re right, you have to put …

John L. Marshall, MD: Well, I think the data are with capecitabine, I would say, so that’s not a cheap drug. And the data are with bevacizumab, too, which is not a cheap drug either.

Wells A. Messersmith, MD, FACP: Yes, true.

John L. Marshall, MD: But do you maintain the EGFR therapy through that or switch? What’s your thought on that?

Marwan Fakih, MD: I do maintain if it’s tolerated by patients. I like to mention the VALENTINO trial showed a PFS of 13 months versus 10 months, and that was statistically significant.

John L. Marshall, MD: So you drop the chemotherapy and just give single-agent EGF?

Marwan Fakih, MD: I drop. I still use FOLFOX in my first-line approach, and I drop oxaliplatin after 4 months of treatment, and then they’re maintained on fluoropyrimidine and anti-EGFR. Now, I do switch biologicals if they have a problem with anti-EGFR toxicity. So if I see the magnesium level is dropping and I can’t keep up with the replacement or it becomes a nuisance to the patient, certainly I have no problems at all at that point, dropping anti-EGFR and switching to fluoropyrimidine-bevacizumab.

John L. Marshall, MD: You know how I’ve solved hypomagnesaemia?

Marwan Fakih, MD: How?

John L. Marshall, MD: I don’t check it. It just goes away. It’s no longer a problem. That’s a good strategy. You just don’t look.

Marwan Fakih, MD: But I’ll tell you, I’ve seen some 0.4s gone.

Wells A. Messersmith, MD, FACP: VALENTINO though looked at continuing panitumumab plus 5-FU versus panitumumab. So it’s the 5-FU that’s the 3-month benefit, not the panitumumab.

Marwan Fakih, MD: But I have to say, 13 months is quite an impressive PFS.

Wells A. Messersmith, MD, FACP: It is, I agree.

Marwan Fakih, MD: So there’s a signal there.

Wells A. Messersmith, MD, FACP: What you’re saying is you are a FIRE believer and not a CALGB/SWOG 80405 believer.

Marwan Fakih, MD: Well, CALGB/SWOG 80405 left colon RAS is not that far from FIRE-3.

Transcript Edited for Clarity 
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